Genetic anticipation in a special form of hypertrophic cardiomyopathy with sudden cardiac death in a family with 74 members across 5 generations

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heritable heart disease. The genetic anticipation of HCM and its associated etiology, sudden cardiac death (SCD), remains unclear. The aim of this study was to investigate the mechanism underlying the genetic anticipation of HCM and associated SCD.An HCM family including 5 generations and 74 members was studied. Two-dimensional echocardiography was performed to diagnose HCM. The age of onset of HCM was defined as the age at first diagnosis according to hospital records. The information on SCD was confirmed by verification by ≥2 family members and a review of hospital records. Whole-genome sequencing was performed on 4 HCM subjects and 1 healthy control in the family. The identified mutations were screened in all available family members and 216 unrelated healthy controls by Sanger sequencing.The median ages of onset of HCM were 63.5, 38.5, and 18.0 years in members of the second, third, and fourth generations of the family, respectively, and the differences between the generations were significant (P < 0.001). The age at SCD also decreased with each subsequent generation (P < 0.05). In particular, among the third-generation family members, SCD occurred between 30 and 40 years of age at approximately 8 AM, whereas among the fourth-generation family members, all 5 males who experienced SCD were 16 years of age and died at approximately 8 AM. The sarcomere gene mutations MYH7-A719H and MYOZ2-L169G were detected in the HCM individuals in this pedigree. Increases in the number of mutations and the frequency of multiple gene mutations were observed in the younger generations. Moreover, a structural variant was present in the HCM phenotype-positive subjects but was absent in the HCM phenotype-negative subjects.HCM may exhibit genetic anticipation, with a decreased age of onset and increased severity in successive generations. Multiple gene mutations may contribute to genetic anticipation in HCM and thus may be of prognostic value.

Figure 1

Pedigree of the HCM family. The white symbols represent healthy individuals, the black symbols represent affected individuals, the squares indicate males, and the circles indicate females. The crossed black symbols represent deceased individuals who died of sudden cardiac death. The crossed white symbols indicate deceased individuals who died of other or unknown causes. The individual indicated by the arrow is the proband. The subjects highlighted by asterisks (II:3, III:15, IV:13, IV:14, and IV:22) were examined by whole-genome sequencing. HCM = hypertrophic cardiomyopathy.

Figure 2

The median age of onset of HCM and median age of SCD across generations. The ages of onset of HCM and SCD were clearly lower in the younger generations. HCM = hypertrophic cardiomyopathy, P^II–III = P value between generations II and III (Wilcoxon rank-sum test), P^III–IV = P value between generations III and IV (Wilcoxon rank-sum test), P^overall = P value among all generations (Kruskal–Wallis test), SCD = sudden cardiac death.

Figure 3

Electropherograms of the identified mutations in the affected HCM patients. Two-dimensional echocardiography in the parasternal left ventricular long-axis view showing increasing hypertrophy in the interventricular septum of the 3 affected individuals. The asterisk indicates the maximum hypertrophy at this site in each individual. Around the echocardiography, the vertical rectangles and the black arrows indicate the sites of the identified mutations. AO = aorta, HCM = hypertrophic cardiomyopathy, LA = left atrium, LV = left ventricle, RV = right ventricle.